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February 2018 Pulmonary Case of the Month
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Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia in a Patient
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First Report of Splenic Abscesses Due to Coccidioidomycosis
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June 2017 Pulmonary Case of the Month
May 2017 Pulmonary Case of the Month
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December 2016 Pulmonary Case of the Month
Inhaler Device Preferences in Older Adults with Chronic Lung Disease
November 2016 Pulmonary Case of the Month
Tobacco Company Campaign Contributions and Congressional Support
   of the Cigar Bill
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September 2016 Pulmonary Case of the Month
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April 2016 Pulmonary Case of the Month
Pulmonary Embolism and Pulmonary Hypertension in the Setting of
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March 2016 Pulmonary Case of the Month
February 2016 Pulmonary Case of the Month
January 2016 Pulmonary Case of the Month
Interval Development of Multiple Sub-Segmental Pulmonary Embolism in
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November 2015 Pulmonary Case of the Month
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Staphylococcus aureus Sternal Osteomyelitis: a Rare Cause of Chest Pain
Safety and Complications of Bronchoscopy in an Adult Intensive Care Unit
October 2015 Pulmonary Case of the Month: I've Heard of Katy


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The Southwest Journal of Pulmonary and Critical Care publishes articles broadly related to pulmonary medicine including thoracic surgery, transplantation, airways disease, pediatric pulmonology, anesthesiolgy, pharmacology, nursing  and more. Manuscripts may be either basic or clinical original investigations or review articles. Potential authors of review articles are encouraged to contact the editors before submission, however, unsolicited review articles will be considered.



COPD Exacerbations: An Evidence-Based Review

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ


COPD exacerbations are a major source of COPD morbidity, mortality and cost. Exacerbations tend to become more frequent as COPD progresses with the cause assumed to be infectious in about 80% of patients. The mainstay of management is inhaled bronchodilators with judicious use of oxygen, antibiotics, corticosteroids and assisted ventilation. Recent studies have examined strategies to prevent exacerbations of COPD including use of macrolide antibiotics and self-management education.

Definition of COPD Exacerbations

There is no standard definition of COPD exacerbations. However, the workshop, “COPD: Working Towards a Greater Understanding”, proposed the following working definition in 2000: “A sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD” (1). This seems to be the mostly commonly used definition today. Others have defined exacerbations specifically in terms of increased dyspnea, sputum production, or sputum purulence (2,3).  However, exacerbations of COPD comprise a range of symptoms making specific medical complaints difficult to include in a comprehensive definition (1).

Epidemiology of COPD Exacerbations

Exacerbations reduce quality of life, speed disease progression, and increase the risk of death (4,5). Furthermore, exacerbations resulting in hospitalization account for the major cost of COPD (6). The best predictor of future exacerbations is a history of frequent exacerbations (7). As many as 50% of exacerbations are not reported to physicians and 3-16% require hospitalization (8). Hospital mortality is 3-10% and mortality of ICU admission is 15-24%.  Half of the patients hospitalized will require readmission in the next 6 months (8).

Frequency of exacerbations increase with increasing severity of COPD. In a systematic review, patients with mild COPD had a mean of 0.82 exacerbations per year (9). The rates increased to 1.17, 1.61, and 2.01 in patients with moderate, severe, and very severe disease, respectively.

COPD is a lung disease that is frequently associated with other comorbid conditions. These comorbidities affect health outcomes, increase the risks of hospital admission, increase the risk of death, and account for more than 50% of use of health-care resources for COPD (10,11). The relationship of certain comorbidities with COPD is not surprising because of COPD’s connection with cigarette smoking and aging. Cigarette smoking is not only a major risk factor for COPD, but also for cardiovascular disease, osteoporosis, and lung cancer and all are more frequently seen in COPD patients (12). Aging is a major risk factor for most chronic diseases including COPD. Almost half of all COPD patients aged 65 years or over have at least three chronic medical disorders (13). Consistent with this concept, a cluster analysis indicated that age rather than FEV₁ accounted for most of the comorbidities and symptoms (14). Furthermore physical inactivity, which is frequently observed in COPD, has been linked to aging and to major comorbidities (15-17). The presence of comorbidities likely explains why clinical outcomes in COPD only weakly correlate with the FEV1 (18).

Another common denominator between COPD and its major comorbidities is systemic inflammation. Increased concentrations of circulating cytokines (tumor necrosis factor α and interleukins 6 and 8), adipokines (leptin, ghrelin), and acute-phase proteins (C-reactive protein, fibrinogen) are seen in COPD and its comorbid diseases (19). In several studies biomarkers of systemic inflammation have been observed in patients with COPD, particularly when disease is severe and during acute exacerbations (19,20).  Whether these systemic markers spill over from the lungs into the systemic circulation or merely reflect the proinflammatory state is unclear (21). However, none of these systemic inflammatory markers have received generalized acceptance in predicting or diagnosing exacerbations.

Etiology of COPD Exacerbations

Several causes of exacerbations have been suggested for patients with COPD, including heart failure, pneumonia, pulmonary embolism, non-adherence to inhaled medication, or inhalation of irritants, such as tobacco smoke or particles (19). However, the most frequent cause cited by most is viral or bacterial infection (19). In patients admitted to hospital with COPD exacerbations, viruses, bacteria or both, were detected in 78% of cases (22). The exacerbations associated with infection were more severe than those in patients with non-infectious causes (22). However, the 80% frequency of infectious causes may be an overestimation.  The accepted gold standard for the diagnosis of bacterial causes is the isolation of a potentially pathogenic bacterium by sputum culture. However, sputum cultures are neither sensitive nor specific. An additional difficulty is that a substantial proportion of patients with stable COPD have bacterial colonization (23). These include the organisms most commonly associated with exacerbations: H. influenzae, S. pneumoniae, and M. catarrhalis.

Viruses are thought to account for 15–25% of all infective exacerbations, particularly human rhinovirus, influenza, parainfluenza, and adenoviruses (19). Infection with both viruses and bacteria are seen in 25% of patients with exacerbations who are admitted to hospital (22).  Viral exacerbations are strongly correlated with colds at presentation, high frequency of exacerbations, and severe respiratory symptoms during exacerbations. Experimental evidence suggests that upper respiratory tract infections can lead to lower respiratory tract inflammation and symptoms. COPD patients experimentally infected in the upper respiratory tract with rhinovirus developed lower respiratory symptoms, airflow obstruction, systemic inflammation, and inflammation in their airways (24). In addition to inducing lower respiratory inflammation and symptoms, viral infections may facilitate subsequent bacterial infection. Although viral infections are usually self-limiting, secondary bacterial infection may prolong exacerbations (24).

Gastroesophageal reflux has been suggested to play an important role in a number of respiratory diseases and has been independently associated with increased frequency of COPD exacerbations (7). Similarly, sleep-apnea has also been shown to be an independent predictor of COPD exacerbations (25).

No serum marker of bacterial or viral infection in COPD exacerbations has gained general acceptance. However, measurements of procalcitonin and C-reactive protein have been suggested as predictors of bacterial infection since both have been shown to predict results to antibiotic therapy (26,27). Increased concentrations of serum interferon-γ-inducible protein10 were useful in identifying rhinovirus infection in one study (28).

A recent publication by Bafadhel et al. (29) measured biomarkers in sputum and serum from a total of 145 COPD patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed “pauciinflammatory.” Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1β, serum CXCL10, and percentage peripheral eosinophils. Future research may establish the usefulness of these as well as other biomarkers in predicting and diagnosing infectious causes of COPD exacerbations.

Diagnostic Interventions in COPD

Clinical judgment is necessary in evaluating the need for hospital admission and which diagnostic tests need to be performed. Patients with mild exacerbations may be managed as outpatients with no diagnostic testing. Patients with more severe exacerbations may need diagnostic testing and hospitalization when appropriate.

Chest x-rays have been found to be useful in evaluation of COPD exacerbations. Data from observational studies show that in 16% to 21% of the chest radiographs change patient management (30-32). Arterial blood gases are helpful in assessing the severity of an exacerbation and the degree of hypoxemia and hypercarbia. The later is particularly important in identifying patients that are likely to require hospitalization and additional ventilatory support (33). Although spirometry and peak flows may be useful in identifying an exacerbation, available evidence does not support their routine measurement to guide therapy during an exacerbation (33).

Treatment of COPD Exacerbations

Therapies for treatment of COPD exacerbations and their evidence basis are summarized in Table 1.  

Table 1. Therapies for COPD exacerbations.

Oxygen. In my practice inappropriate empiric use of high doses of oxygen was becoming increasingly problematic. High doses of oxygen can result in absorption atelectasis, increased ventilation-perfusion mismatch and increased hypercarbia. The British Thoracic Society (BTS) has published guidelines that oxygen is a treatment for hypoxemia, not breathlessness or dyspnea (34). Oxygen has not been shown to affect breathlessness in nonhypoxemic patients, and therefore, empirically increasing oxygen administration for breathlessness when the oxygen saturation is satisfactory is ineffective and potentially harmful. BTS suggests oxygen should be prescribed to achieve a target saturation of 94-98% for most acutely ill patients or 88-92% for those at risk for hypercapnic respiratory failure. Hypercapnic patients at high risk for respiratory failure may usually be safely managed with oxygen saturations as low as 85-88%.

In support of the concept that empiric use of high flow oxygen may do more harm than good, Austin et al. (35) compared nontitrated high flow oxygen with titrated oxygen in the prehospital setting in COPD patients with an acute exacerbation. Those administered oxygen to a titrated oxygen saturation of 88-92% had reduced mortality, hypercapnia and respiratory acidosis compared to those treated with nontitrated oxygen at 8-10 L/min.

It appears to make little difference if oxygen is administered by nasal cannula or Venturi mask. In a study comparing patients assigned to receive oxygen through a Venturi mask or nasal prongs oxygen saturation improved to the same extent without any significant effect upon arterial carbon dioxide tension or pH (36).

Bronchodilators. The first line of treatment for a COPD exacerbation is to increase the frequency of short-acting inhaled beta 2-agonists and/or anticholinergics. However, there are only four randomized, controlled trials comparing beta 2-agonists with anticholinergics and all analyzed short-term effects (37). Overall, the available data show similar FEV1 improvement with either bronchodilator. Although use of both in combination is common, there does not appear to be strong evidence to support this approach (37,38). There is very limited data on use of long-acting beta 2-agonists (formoterol and salmeterol) or long-acting anticholinergics (tiotropium) in treatment of exacerbations of COPD.  

Metered-dose inhaler (MDI) and small volume nebulizers appear to be equivalent in the acute treatment of adults with airflow obstruction (39). It is assumed that the cost of delivery is lower with MDIs due to decreased nursing or respiratory therapist time needed to administer the drugs. Spacer devices have been used with an MDI in most studies.

Thirty years ago methylxanthines, such as aminophylline, were the mainstay therapy for COPD exacerbations. However, these drugs have largely fallen out of favor. A meta-analysis on use of methylxanthines in acute COPD exacerbation did not find any evidence to support their use (40). Methylxanthines do not significantly improve FEV1 during COPD exacerbations and have a narrow therapeutic window with numerous potential side effects including nausea, vomiting, headache, arrhythmias, and seizures.

Corticosteroids. Corticosteroids significantly reduce the risk of treatment failure and length of hospital stay (41). Although the optimal dosage and length of therapy are unknown, the largest trial used methylprednisolone 125 mg intravenously every 6 hours for 72 hours (42). Two weeks of oral prednisone after intravenous therapy was as efficacious as 8 weeks (40). In a retrospective review among patients hospitalized with COPD exacerbations, oral therapy was not associated with worse outcomes compared to high-dose intravenous therapy (43).  

Antibiotics. As previously mentioned, infectious etiologies may account for as many as 80% of the acute COPD exacerbations (19,22). Therefore, it is reasonable to expect that antibiotics would be efficacious. Studies going back to the 1980’s show a significant benefit of antibiotic treatment, with a success rate of 68% for the antibiotic group compared to 55% for the placebo group (2). Subsequent meta-analyses have confirmed these findings (33,44,45). Patients with more severe exacerbations are more likely to benefit from antibiotics than those with milder exacerbations. The presence of purulent sputum may be predictive of the presence of active infection and identify those patients most likely to benefit from antibiotic therapy (46).       

Controversy exists regarding the choice of the newer, broad-spectrum antibiotics compared to the older, traditional antibiotics. Some studies have found significantly higher persistence or worsening of symptoms in patients treated with first-line agents (amoxicillin, cotrimoxazole, tetracyclines, or erythromycin) compared to second or third-line agents (amoxicillin/clavulanate, azithromycin, or ciprofloxacin) (47,48). On the other hand, other studies suggest that host factors rather than antibiotic choice are the primary determinants of treatment failure (49). It may be that the anti-inflammatory effects of certain antibiotics such as the macrolides or tetracyclines account for some of the variability (50,51). Recently a concern has been raised regarding macrolides causing QT prolongation and a very small, but significant, increase in cardiovascular death (52). Tetracyclines such as doxycycline may represent an alternative to the macrolides since they do not cause QT prolongation

The duration of antibiotic therapy is also controversial. However, a recent meta-analysis by El Moussaoui et al. (53) suggests that 5 days of therapy is as effective as longer durations of therapy.

Other Pharmacologic Agents. A variety of mucolytics, mucokinetics, expectorants, antiproteases, antioxidants and immunostimulants have been proposed to treat COPD exacerbations but do not have well established clinical efficacy (54). A review of mucolytic agents in acute exacerbations of COPD suggested there was no evidence that they shortened the duration of the exacerbations or improved the FEV1 (55). However, the analysis did suggest that mucolytics might improve symptoms compared to controls. In the nonacute COPD setting, a meta-analysis has found a small reduction in the number of acute exacerbations and days of illness when mucolytics were routinely used (55).

Chest Physiotherapy. During acute COPD exacerbations mechanical percussion of the chest as applied by physical/respiratory therapists is ineffective in improving symptoms or lung function, although it may increase the amount of sputum expectorated (38,56). Furthermore, there may be a transient worsening in FEV1 after chest percussion (38).

Noninvasive Positive-Pressure Ventilation (NIPPV). Noninvasive positive pressure ventilation (NIPPV) is probably the largest therapeutic advance in treating COPD exacerbations in the past 20 years. Meta-analysis has found not only a reduction in the need for intubation and mechanical ventilation with NIPPV, but also a reduction in the risk of death (57). Patients hospitalized for exacerbations of COPD with rapid clinical deterioration should be considered candidates for NIPPV. However, there are no standardized criteria to predict which patients will benefit. Therefore, careful observation, usually in the intensive care unit, is necessary should NIPPV fail.

Heliox. Helium is a low density inert gas that in combination with oxygen (heliox) has been used as an additive treatment in upper airway obstructions and other causes of respiratory failure. The rationale for its use during COPD exacerbations is to diminish respiratory effort, peak pressure, and intrinsic positive end expiratory pressure. A meta-analysis in 2002 evaluated the limited literature on the use of heliox in acute COPD exacerbations and concluded that there is insufficient data to support its use (58). A recent randomized trial failed to show heliox reduced intubation rates, duration of noninvasive ventilation, length of stay, complications or 28-day mortality (59). Furthermore, heliox has the disadvantage of coming in fixed concentrations of oxygen sometimes making its use problematic especially in hypercarbic patients.

Reduction of COPD Exacerbations

Continuous therapies for reduction of COPD exacerbations are shown in Table 2.

Table 2. Continuous therapies for reduction of COPD exacerbations.

Bronchodilators. Many of the therapies that treat COPD exacerbations have been tested to determine if chronic use might prevent exacerbations. The best evidence is for the long-acting bronchodilators. Two large randomized controlled trials have confirmed that a combination of a long-acting beta agonist (salmeterol) with an inhaled corticosteroid (fluticasone) or a long-acting anticholinergic (tiotropium) reduce exacerbations (60,61). Both appear to appear to be similarly efficacious in exacerbation reduction (62).

Research is being done with several new bronchodilators to treat COPD. Roflumilast, an oral specific phosphodiesterase 4 inhibitor, reduced the frequency of exacerbations by 17% in patients with severe or very severe COPD (63). Reductions are also seen with the addition of roflumilast to salmeterol or tiotropium (64). Several new, once-daily, long-acting beta-agonists and anticholinergics are under development and being tested alone or in combination. Indacaterol, a once daily beta-agonist, is the first of these once daily beta-agonists to become clinically available. It is anticipated that these will also reduce exacerbations similar to salmeterol/fluticasone or tiotropium.

Since both long-acting anticholinergics and long-acting beta-agonists/inhaled corticosteroids reduce exacerbations, it is logical that a combination might be additive in reducing exacerbations of COPD. However, a recent study suggests that addition of salmeterol/fluticasone to tiotropium was ineffective compared to tiotropium alone in reducing exacerbations although FEV1 and albuterol use were improved (65).

Inhaled corticosteroids. Addition of inhaled corticosteroids to long-acting bronchodilators in COPD is controversial. A recent meta-analysis by Spencer et al. (66) suggests that there was no reduction in exacerbations with addition of an inhaled corticosteroid to a long-acting beta-agonist. Furthermore, addition of corticosteroids was associated with a higher incidence of pneumonia. On the other hand, a retrospective, observational study suggested that the use of inhaled corticosteroids prior to a COPD exacerbation resulted in reduced mortality (67). In elderly COPD patients without a history of an exacerbation addition of inhaled corticosteroids was not associated with improved outcomes (68). This suggests that if inhaled corticosteroids are efficacious, they may only be efficacious in patients with a history of exacerbations.

Antibiotics. Continuous treatment with some antibiotics, particularly macrolides, reduces exacerbations. A randomized controlled trial with erythromycin reduced exacerbations by 35% compared to placebo (69). In a more recent study, treatment with azithromycin for one year lowered exacerbations by 27% (70). Although the mechanism(s) accounting for the reduction in exacerbations is unknown, current concepts suggest the reduction is likely secondary to the macrolides’ anti-inflammatory properties. However, concern has been raised about a very small, but significant, increase in QT prolongation and cardiovascular deaths with azithromycin (52). In addition, the recent trial with azithromycin raised the concern of hearing loss which occurred in 25% of patients treated with azithromycin compared to 20% of control (70). An alternative to the macrolides may be tetracyclines such as doxycycline, which also possess anti-inflammatory properties but do not lengthen QT intervals nor cause hearing loss (50).

Immunizations. Until recently, the only pneumococcal vaccine approved for use in adults in the United States and Europe was the 23-valent pneumococcal polysaccharide vaccine (PPSV23). This is despite no randomized, controlled trial of the vaccine showing a reduction in clinical outcomes (71). Recently a 7-valent diphtheria-conjugated pneumococcal vaccine has been approved for use in adults. This conjugated vaccine induces greater serotype-specific immunoglobulin G (IgG) and functional antibody than does PPSV23 for up to 2 years after vaccination (72). Whether these increases in surrogate markers will translate into lower rates of COPD exacerbations is unknown.

It appears, from the limited number of studies performed, that influenza vaccine reduces exacerbations in COPD patients (73). The effect appears to be due to a reduction in exacerbations occurring three or more weeks after vaccination due to influenza. There is a mild increase in transient local adverse effects with influenza vaccination, but no evidence that vaccination increases exacerbations immediately after administration.

Other approaches. Pulmonary rehabilitation and self-management education programs reduce hospitalization for COPD exacerbations (74, 75).  A recent study found increased mortality with COPD self-management education (76) but this was not confirmed by meta-analysis (75). Lung volume reduction surgery, an approach to severe COPD, was surprisingly found to reduce exacerbation frequency (77). The cause of the reduction is unknown but may reflect the benefits of reducing hyperinflation. A specific effect of long-term oxygen in appropriate patients on reducing exacerbations has not been demonstrated. However, there is evidence that underuse of long-term oxygen therapy results in increased hospital admissions (78).  Vitamin D levels have been found to be reduced in some patients with COPD. However, treatment with vitamin D did not improve exacerbation rates except those with severe vitamin D deficiency (serum 25-[OH]D levels <10 ng/mL) (79).

Clinical Approaches

Outpatient. Based on the available evidence, my approach was to prescribe antibiotics and prednisone for home use during an exacerbation to most patients with severe or very severe COPD (FEV1 < 50% predicted) and patients with moderate COPD who had been hospitalized or had frequent exacerbations. Most severe and very severe COPD patients were also treated with long-acting bronchodilators and an albuterol rescue inhaler. Many were treated with a combination of both a long-acting beta agonist (salmeterol or formoterol) with an inhaled corticosteroid and a long-acting anticholinergic. Patients with mild exacerbations were treated as outpatients with antibiotics (usually doxycycline) and oral prednisone. Prednisone was given as a fixed dose (usually 15 mg/day) for 7-14 days since tapering with short-term use is unnecessary (80). Some patients with frequent exacerbations were prescribed chronic doxycycline therapy in hopes of reducing exacerbations. Most received pulmonary rehabilitation and therapy for smoking cessation if needed.

It is usually appropriate to initiate discussions about end of life planning with a COPD patient as an outpatient (81). Autonomy of the patient is the predominant ethical principle that drives end-of-life care. These discussions should prepare patients with advanced COPD for a life-threatening exacerbation of their chronic disease. Discussions should include ICU admission and intubation and mechanical ventilation using data where appropriate to assist in the decision. Pulmonary rehabilitation provides an important opportunity to assist advance care planning for patients with moderate-to-severe COPD. Patients with COPD sometimes qualify for formal hospice services, especially when they are having repeated exacerbations and poor clinical function. Opportunities for hospice care are frequently neglected for patients coming to the end of life with COPD. Morphine is the drug of choice for the relief of dyspnea and in selected patients chronic positive pressure ventilation may be used (82).

Inpatient. My rationale was that if a patient was sick enough to be in the hospital, he was sick enough to receive bronchodilators, antibiotics, and corticosteroids. Chest x-rays and arterial blood gases were routinely performed on hospitalized patients. Those with hypercarbia and respiratory acidosis were usually admitted to the ICU and especially those with an exacerbation sufficiently severe to require noninvasive positive pressure ventilation. Oxygen was titrated to maintain the SpO2 at 88-92%, and if severe respiratory acidosis was present, oxygen was titrated to a SpO2 of 85-88%.  Albuterol by MDI was used as often as needed to control symptoms, sometimes as often as every 1-2 hours with careful monitoring. Ipratropium by MDI was added if the patients were not receiving tiotropium. If the patients were taking long-acting bronchodilators as outpatients, these were continued during inpatient hospitalization. Doxycycline was used as an antibiotic in the absence of culture evidence or x-ray evidence to choose an alternative. Corticosteroids were given as methylprednisolone 125 mg IV every 6 hours for 3 days and then oral prednisone for another 2 weeks. Rarely, methylxanthines were added in those very severe patients who failed to clinically improve in 1-3 days. Those who were not on long-acting bronchodilators were started on one or both prior to discharge to reduce the number of future exacerbations. Patients were followed up in the outpatient clinic about 2-3 weeks after hospital discharge.


COPD exacerbations are common and can often be managed as outpatients with careful planning and education in self-management. Communication between the patient and physician regarding end of life planning is useful in planning future care during a severe exacerbation. Most patients can be managed with inhaled bronchodilators, antibiotics and corticosteroids. Titration of oxygen or administration of NIPPV usually requires hospitalization, especially in hypercarbic patients.


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Reference as: Robbins RA. COPD exacerbations: an evidence-based review. Southwest J Pulm Crit Care 2012;5:36-51. (Click here for a PDF version of the manuscript)


July 2012 Pulmonary Case of the Month: Pulmonary Infiltrates - Getting to the Heart of the Problem

Bridgett Ronan, MD

Robert Viggiano, MD

Lewis J. Wesselius, MD


Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ


History of Present Illness

A 63 year old man was transferred from outside facility with ventricular tachycardia. He has a past history of ventricular tachycardia and had an intracardiac defibrillator (ICD) placed due to a low ejection fraction. The ICD had administered several shocks to the patient prior to admission.

His present medications included:

  • Lisinopril 10 mg bid
  • Diazepam 10 mg bid
  • Amiodarone 400 mg daily
  • Dutasteride 0.5 mg daily
  • Tamsulosin 0.4 mg daily
  • Dexlansoprazole 60 mg daily
  • Levothyroxine 100 mcg daily

The patient underwent and electrophysiology (EP) procedure. He was intubated prior to the procedure. He developed sustained ventricular tachycardia when the ICD was turned off. Eleven cardioversions were required with an accumulated 108 seconds of ventricular tachycardia. He became hypotensive and received 6.2 L boluses of fluids and 5, 400 mg boluses of amiodarone and was placed on an amiodarone drip.

He remained intubated receiving mechanical ventilator after the EP procedure.

He was extubated after 2 days and was initially on oxygen at 6L/min nasal cannula. Over the next several days he developed increasing oxygen requirements and was treated with BiPAP and increasing oxygen.

PMH, SH and FH

As noted above he had a history of recurrent ventricular tachycardia and a dilated cardiomyopathy with an ejection fraction of 30-35%. In addition he had a history of paroxysmal atrial fibrillation, obstructive sleep apnea which resolved with weight loss, hypothyroidism and mild restriction on pulmonary function testing, possibly related to amiodarone or to kyphosis. He is a life-long nonsmoker.

Physical Examination

His vital signs included a Tmax of 38.8 C, heart rate of  79 beats/min, blood pressure of  113/67 mm Hg, respiratory rate of 38 breaths/min, and oxygen saturation of 94% on a 75% high flow mask. His weight had increased to 102 kg from 96.6 kg on admission.

Cardiovascular exam revealed an irregular rhythm but no murmur. There was jugular venous distention present. There was a trace of pedal edema but deeper pitting edema at the hips.

Pulmonary auscultation revealed bilateral rales with diminished breath sounds at the bases.

Chest X-ray

Admission and current chest x-ray are shown in Figure 1.

Figure 1. Admission chest x-ray (panel A) and current chest x-ray (panel B).

Laboratory Evaluation

Arterial blood gases showed a pH of 7.42, a pCO2 of 39 and a pO2 of 73 on 70% FiO2. The white blood cell count (WBC) was elevated at 15.1X103 cells/mm3.

Which of the following could explain the patient’s increased oxygen requirements?

  1. Pulmonary edema
  2. Pneumonia
  3. Amiodarone lung toxicity
  4. A + B
  5. A + C
  6. All of the above

Reference as: Ronan B, Viggiano R, Wesselius LJ. July 2012 pulmonary case of the month: pulmonary infiltrates - getting to the heart of the problem. Southwest J Pulm Crit Care 2012;5:1-11. (click here for a PDF version of the case)


Cough and Pleural Disease in a Burmese Immigrant – A Masquerader

George M. Solomon, MD1

Eric Schmidt, MD1,2

Randall Reves, MD3

Carolyn Welsh, MD1


Department of Medicine, Divisions of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver1

Denver Health Medical Center2

Denver Metro Tuberculosis Control Program, Denver Public Health Department3


Corresponding Author:         George M. Solomon, MD

                                          Research Building 2

                                          9th Floor12700 E. 19th Ave

                                          Aurora, Colorado 80045

                                          Phone 303-398-1392


Financial Disclosures: No authors report any financial conflicts to disclose



We present a case of a 58 year old Burmese male who presented to our center with progressive pulmonary and constitutional symptoms after treatment for pulmonary tuberculosis. Our investigation revealed peripheral and bronchogenic eosinophilia and clinical features consistent with progressive pulmonary paragonimiasis. After serological confirmation of the diagnosis, the patient had resolution of symptoms with praziaquantel therapy for the condition.  This case highlights the importance of considering this diagnosis when there is a possibility of undercooked shellfish exposure especially in immigrants from endemic areas for paragonimiasis where raw shellfish is more commonly ingested.

Case Presentation 

A 58 year old Burmese male was referred for evaluation of cough and pleural abnormalities on a chest radiograph.  The patient had arrived in Boston as a Burmese refugee the previous year.  Upon arrival in the United States, he was found to have a right middle lobe infiltrate, multiple cavitary nodules on chest CT, three negative sputum AFB smears and 10 mm induration on Mantoux tuberculin skin testing.  He was treated with rifampin, isoniazid, pyrazinamide, and ethambutol for 2 months with resolution of the cavitary nodules but developed an increasing right pleural opacity. Sputum cultures were negative for mycobacteria.

He moved to Denver, Colorado where an additional four months of isoniazid and rifampin were completed for presumed culture negative pulmonary tuberculosis. At the end of treatment he noted an increase in his persistent cough and fatigue associated with low grade fevers.  A repeat chest radiograph now revealed a small right-sided pleural effusion (Figure 1).

Figure 1. Chest radiograph demonstrating right-sided small pleural effusion

Assessment at the pulmonary clinic revealed persistent cough and a 6.8 kg weight loss.  Physical examination was pertinent for a temperature of 99.0 ºF, dullness to percussion and crackles in the right lung.  The patient reported occasional tobacco use and reported occasional raw seafood consumption in Burma.  He denied other medical history at this time except for untreated hypertension. 

Laboratory investigation was pertinent for a white blood cell count of 10,000 per µl with a differential of 22% eosinophils and normal platelet and hemoglobin levels. Anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), and rheumatoid factor levels as well as a comprehensive metabolic profile and coagulation labs were all normal. 

Computed tomography of the chest at the time of presentation to the pulmonary clinic compared to the one a year earlier in Boston are shown in Figure 2.

Figure 2. A. Computed Tomography image of the chest demonstrating right middle lobe opacification and pleural effusion at presentation to the pulmonary clinic. B. Computed Tomography image of the chest at time of initial treatment in Boston demonstrating right-sided cavitary disease and pleural process.

Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) revealed 960 nucleated cells, 68% of which were eosinophils.  Routine cultures grew normal oral flora and were negative for actinomyces, fungi and mycobacteria.  Wet prep for oocysts and larvae was negative. 

Ultrasound revealed only a small loculated pleural effusion, precluding thoracentesis.

Because of suspicion for parasitic illness, a filarial antibody panel was also sent and was negative. Paragonimus antibody immunoblot assay was positive.

Case Follow-up

The patient was treated with praziquantel 25 mg/kg orally three times daily for 3 days with improvement in symptoms and radiographic abnormalities as show in Figure 3. 

Figure 3. Chest radiograph following treatment with praziquantel demonstrating resolution of resolving right-sided pleural effusion and right-sided infiltrates.


Paragonimiasis results from infection by one of the more than fifty species of the genus paragonimus (most commonly P. westermanii).  There are approximately 2.5 million cases annually reported in endemic areas, mostly in Indo-China and sub-Saharan Africa.  In the western world, most cases are reported in immigrants from endemic regions where undercooked shellfish are culturally consumed.  Approximately 50-70% of infections are initially diagnosed as tuberculosis in the U.S. (1), as demonstrated in this case.  

The lifecycle of the organism begins with early ingestion and early disease characterized by cough, fever, and pleuritic chest pain resulting from a transdiaphragmatic spread of larvae into the pleural space from the abdomen.  Prominent features of this “early” disease are pneumothorax or pleural effusion and peripheral eosinophilia (2).  Additionally, transient pulmonary infiltrates may be observed. This presentation may help to explain the response of parenchymal abnormalities in response to the anti-tuberculosis treatments.  In fact, the “response” to treatment may have been a consequence of the natural history of early stage paragonimiasis. 

The failure of resolution of pleural disease in this case to anti-tuberculosis drugs should have alerted clinicians to consider alternative diagnoses.  The progressive pleural disease in this case while on anti-tuberculosis drugs highlights progression of paragonimiasis pulmonary disease.  “Late” stage lung disease results from mature fluke inhabitation in the lung parenchyma. During this phase, patients typically resolve their peripheral eosinophilia and fever but may have persistent dark brown hemoptysis.   Radiographic features in this stage are varied and include parenchymal mass-like lesions or chronic pleural lesions (2).

If paragonimiasis is suspected, diagnosis is most readily made by serological evaluation. Heretofore, microscopic evaluation of oocysts and larvae from sputum or BAL yielded a diagnosis in only 50-75% of cases (3).  Serological evaluations including immunoblot assays for P. Westermanii antibodies have a reported sensitivity of 96% and specificity of 99% (4) and ELISA-based assays have a reported sensitivity of 92% and specificity of 90% (5); thereby, these assays have therefore largely supplanted other microscopic evaluation given the superior diagnostic performance

Treatment regimens are nearly 100% effective in cure for pulmonary disease. Typical regimens include three days of praziquantel therapy at 25mg/kg given three times daily. It is additionally important to counsel patients and their families on avoidance of raw seafood as well as contact prophylaxis, as cross-contamination from soiled utensils can result in illness to others (6).  A recent case series of locally-acquired paragonimiasis from undercooked river shellfish in the U.S. acquired from undercooked shellfish in restaurants (7) further highlights the importance of considering this diagnosis especially if the history of potential exposure is substantiated, thus raising awareness of paragonimiasis infection as a potential public health hazard in food/beverage establishments. 

In summary, paragonimiasis is a relatively common infection in endemic areas of the world. Infection is often mistaken as tuberculosis in immigrants to the western world. However, knowledge of the clinicopathologic features of the disease should lead to appropriate consideration and treatment for at-risk patients. 


  1. Kagawa FT. Pulmonary paragonimiasis. Seminars in Respiratory Infections 1997;12:149-158.
  2. Mukae H, Taniguchi H, Matsumoto N, Iiboshi H, Ashitani J, Matsukura S, Nawa Y. Clinicoradiologic features of pleuropulmonary paragonimus westermani on Kyusyu Island, Japan. Chest 2001;120:514-520.
  3. Khan R, Sharma OP. Bronchial lavage in tropical pneumonias. Curr Opin Pulm Med 2007;13:225-229.
  4. Slemenda SB, Maddison SE, Jong EC, Moore DD. Diagnosis of paragonimiasis by immunoblot. Am J Trop Med Hyg 1988;39:469-471.
  5. Imai J. Evaluation of elisa for the diagnosis of paragonimiasis westermani. Trans R Soc Trop Med Hyg 1987;81:3-6.
  6. Johnson RJ, Jong EC, Dunning SB, Carberry WL, Minshew BH. Paragonimiasis: Diagnosis and the use of praziquantel in treatment. Reviews of infectious diseases 1985;7:200-206.
  7. Human paragonimiasis after eating raw or undercooked crayfish --- Missouri, July 2006-September 2010. MMWR 2010;59:1573-1576.

Reference as: Solomon GM, Schmidt E, Reves R, Welsh C. Cough and pleural disease in a Burmese immigrant-a masquerader. Southwest J Pulm Crit Care 2012;4:205-10. (Click here for a PDF version of the manuscript)


Meta-Analysis of Self-Management Education for Patients with Chronic Obstructive Pulmonary Disease

Jessica Hurley, MD1

Richard D. Gerkin, MD1

Bonnie Fahy, RN, MN2

Richard A. Robbins, MD2* 

Good Samaritan Regional Medical Center1 and the Phoenix Pulmonary and Critical Care Research and Education Foundation2, Phoenix, AZ




Chronic obstructive pulmonary disease (COPD) is a common disease frequently associated with high use of health services. Self-management education is a term applied to programs aimed at teaching patients skills that promote the self-efficacy needed to carry out medical regimens specific to control their disease. In COPD, the value of self-management education is not yet clear and a recent trial was terminated early because of excess mortality in the intervention group.


The objective of this meta-analysis was to assess the settings, methods and efficacy of COPD self-management education programs on patient outcomes and healthcare utilization.

Selection criteria

Randomized controlled trials of self-management education in patients with COPD were identified. Studies focusing primarily on comprehensive pulmonary rehabilitation (education and exercise) and studies without usual care as a control group were excluded.

Search strategy

We searched PubMed (January 1985 to May 2012) as well as other meta-analysis and reviews.

Data collection and analysis

Two reviewers (JH and RAR) independently assessed study quality and extracted data. Investigators were contacted for additional information.

Main results

The reviewers included 3 group comparisons drawn from 12 trials. The studies showed no significant change in mortality, with one study being an outlier compared to the others.  However, the meta-analysis revealed a reduction in the probability of hospital admission among patients receiving self-management education compared to those receiving usual care.


It is likely that self-management education is associated with a reduction in hospital admissions with no change in mortality. However, because of heterogeneity in interventions, study populations, follow-up time, and outcome measures, data are still insufficient to formulate clear recommendations regarding the preferred curriculum and delivery method of self-management education programs in COPD.


Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death and the only one of the top 5 causes of death that is increasing (1).  The economic and social burden of the disease is immense. The patient usually suffers progressive disability with frequent hospitalizations and emergency room visits. Hospitalizations and emergency room visits account for much of the health care costs from COPD, and therefore, strategies to decrease the these outcomes have received considerable attention (2,3). 

One strategy to improve COPD care has been self-management education, a term applied to any formalized patient education program aimed at increasing knowledge and teaching skills that increase self-efficacy, thus improving collaboration with their healthcare provider to optimally manage patient care. Similar strategies have been successful in other chronic diseases (4-6). However, the effects of self-management programs in COPD, although encouraging, are still unclear (7). Furthermore, a recent trial was terminated prior to enrollment of the planned number of subjects because of excess mortality in the intervention group receiving self-management education (8).

Prompted by the surprising result of an increase in mortality, we reexamined health care outcomes for COPD self-management education by meta-analysis. We found no significant change in mortality but significant reductions in hospitalizations.


Criteria for considering studies for this review

Types of Studies: Only randomized controlled trials evaluating the effect of self-management education on patients with COPD were used.  Every study included some form of patient education that addressed COPD disease self-management. For inclusion, the study must also include a control group that received usual care and were excluded from the interventional self-management education.  Studies prior to 1985 were not included since medical management for COPD differed from current practice guidelines. 

Types of study participants: Only patients with a clinical diagnosis with COPD were included.  Spirometry was not required to be reported in the study to determine the diagnosis of COPD if the patients admitted had previously been diagnosed with COPD by the referring physician. Patients with a sole diagnosis of asthma or reactive airway disease were excluded from this review.

Types of interventions: In order to qualify as an intervention, the primary goal of the study had to center on improving the patient’s fundamental knowledge and understanding of the disease process and self-management of COPD. The methods of information delivery were highly variable and included written, verbal, visual, and/or audio communication.

Types of outcomes measured: The outcomes identified in studies that were included in this review include mortality, hospital admissions, and emergency room visits.

Search methods

Two separate reviewers (JH, RAR) used systematic searches via the information databases including PubMed.  The terms used to search included “COPD” in addition to one of the following words or phrases: “educat*” or “education” or “patient-educat*” or “patient-education” or “patient educat*” or “patient-education” or “self-manag*” or “self-management” or “self manag*” or “self management” or “disease manag*” or “disease management”.  The searches are current through May of 2012. 

Data collection and analysis

Selection of studies: The two reviewers placed successfully retrieved articles using the above search criteria into 3 categories:

  1. Include: RCT evaluating COPD patients and self-management education versus usual care
  2. Possibly Include: RCT evaluating COPD patients and disease education but more information needed beyond what is available in the abstract
  3. Exclude: not an RCT, not focused on self-management of COPD or did not include usual care comparison or primary outcome focused solely on pulmonary rehabilitation

Data extraction: Information from the accepted studies was collected and included: number of patients in the control and interventional groups, type of intervention used (i.e. disease education, medication instructions, pharmacy action plans), length of study until primary outcome, mortality of each group, respiratory-related hospital admissions, and respiratory-related ED visits.

Data analysis:

Publication bias:  Funnel plots were constructed to examine the pattern of study effects by study size.  Outliers on the plot with respect to a 95% confidence interval were also determined.

Assessment of heterogeneity: The I square statistic was used to examine variability in study results.  If I square was greater than 20%, sensitivity analysis was conducted to determine, if possible, the source of heterogeneity.

Data synthesis:  Continuous outcomes were analyzed using weighted mean difference with 95% confidence intervals.  For dichotomous outcomes, a pooled odds ratio was used.  A fixed effects model was used if I square was less than 20%.  A random effects model, using the technique of DerSimonian and Laird (20), was used if I square was greater than 20 %.

RevMan 5.1. (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011) was used for the analysis.


Results of the search: Searches identified 1904 titles and abstracts that were screened to identify 71 potentially relevant articles about self-management education in COPD. Full-text versions of these papers were obtained, and independently assessed by two reviewers (JH and RAR). These were searched for data on mortality, hospitalizations and emergency room (ER) visits.  A total of 12 trials were identified which met the review entry criteria (8-19).

Subjects: A total of 2476 patients were randomized in the 12 studies. The studies were heterogenous with some recruiting patients from outpatient clinics, some from general practice, some from inpatient hospital admissions for COPD exacerbations and some from several sources.

Interventions: All 12 studies described COPD self-management education compared with usual care. The educational delivery mode consisted of group education or individual education. Educational topics varied, as did the discipline of the provider. The follow-up time was variable ranging from 2-12 months.

Comparisons: Twelve studies that compared self-management education with usual care have been included in this review. In one study two intervention groups and one usual care group were used (11). The intervention groups were considered sufficiently similar to be combined.

Outcomes: Reported outcome categories were variable. Studies included in the review identified mortality (10 studies), respiratory-related hospital admissions (9 studies) and emergency room (ER) visits (4 studies).

Missing data: Additional data was requested from the two most recent studies (8,9). A reply was received from one author and is listed in the acknowledgement section.

Mortality: Ten studies reporting mortality were included in the meta-analysis (8-15,18,19). There was no significant difference in mortality between the usual care and intervention groups (OR 0.76; 95% CI (0.44 to 1.30); Figure 1; p=0.31).

Figure 1.  Forest plot of mortality

The level of statistical heterogeneity for this outcome (I square = 54%) may be related to the outlying effect from the report by Fan et al. (8), since its removal led to a lower I square statistic (0%). Also removal of the study resulted in a statistically significant improvement in mortality rate (OR 0.64; 95% CI 0.46 to 0.90)

Respiratory-related Hospital admissions: Nine studies reporting COPD-related hospital admissions were included in the meta-analysis (8-11,13-16,18). There was little heterogeneity present (I square = 0%).  There was a clinically and statistically significant reduction of the probability of at least one hospital admission among patients receiving self-management education compared to those receiving usual care (OR 0.76; 95% CI (0.65 to 0.88); p< 0.001; Figure 2).


Figure 2. Forest plot of pulmonary hospitalization

Emergency room visits: Four trials that reported the effect of self-management education on Emergency Room (ER) visits related to COPD were included in the meta-analysis (9,11,12,17). Although the level of heterogeneity was high (I square = 83%), removal of any one study had little effect on this variability.  There was no significant difference between patients receiving self-management education compared to those receiving usual care in the average number of respiratory-related emergency room visits (Mean difference 0.12/pt-yr; 95% CI (-0.21 to 0.46): p=0.47; Figure 3).

Figure 3. Forest plot of pulmonary emergency room visits/pt-yr.


This meta-analysis systematically evaluated comparisons of self-management education for patients with COPD compared to usual care. The review was prompted by a recent report of increased mortality in patients receiving COPD education (8). Meta-analysis did not confirm an increase in mortality and determined the recent study had significant heterogeneity compared to the other studies.  We confirm a previous meta-analysis which demonstrated a significant decrease in COPD-related hospitalizations in the intervention groups (7). 

Self-management education has been successfully utilized in a number of chronic diseases (4-6). Education including the use of pre-defined action plans may lead to faster and more frequent treatment of COPD exacerbations, thus resulting in the reduction in hospitalizations. Although we did not review cost-effectiveness, hospitalizations represent the major cost of COPD care (2,3). Therefore, self-management education is likely cost-effective. In support of this concept, a recent cost-effective analysis of one successful self-management education program revealed an average cost savings of $593 per patient (21).

This review has a number of limitations. First, there was variation in the intervention content and delivery. Some studies included action plans in the self-management curriculum and others incorporated additional components of pulmonary rehabilitation including exercise. The type and intensity of education delivery varied from one-on-one instruction, group interaction and the distribution of written material.

Second, the COPD-population was defined in varying detail, with studies using very diverse inclusion criteria. As a result, heterogeneity in disease severity was present. This may explain some of the differing results, including the increase in mortality observed in the recently published study (8).

Third, the studies assessed a broad spectrum of outcome measures and length of follow-up. Often meta-analyses could not be performed because of different outcome measures utilized or different methodology used to calculate the same outcome (e.g. ER visits). This lack of data consistency hampered statistical combination and therefore may have biased the estimates in the review.  Since self-management programs are intended to achieve behavioral changes, follow-up should ideally be long term and this was not the case in all studies.

The final limitation was that knowledge of one’s disease does not necessarily lead to behavioral change. It is unclear at this point if the educational programs lead to an increase in healthy behaviors.

The results of the study by Fan et al. (8) showing an increase in mortality is not confirmed by this meta-analysis. Fan’s manuscript describes the BREATH trial which was a randomized, controlled, multi-center trial performed at 20 VA medical centers comparing an educational comprehensive care management program to guideline-based usual care for patients with chronic obstructive pulmonary disease. The intervention included COPD education during 4 individual and 1 group sessions, an action plan for identification and treatment of exacerbations, and scheduled proactive telephone calls for case management. It is unclear why this education and self-management which is not very dissimilar from other studies would increase mortality. Although the patients were recruited after they were hospitalized, and therefore, likely had more advanced COPD than in some other studies, this alone should not explain excess mortality in the intervention group. An accompanying editorial by Pocock in the same issue of the Annals of Internal Medicine identified no apparent reason for the increase in mortality and points out that education seems an unlikely cause (22). We also have been unable to identify an explanation for the increase and agree with Pocock that the reason seems most likely secondary to statistical chance. The present meta-analysis is consistent with this concept.

For future research of the efficacy of self-management education of COPD patients in improving patient outcomes and decreasing health care utilization, it is important to create more homogeneity in the design of the studies (educational curriculum, demographics, outcome measures and follow-up period). The effectiveness of the individual components of self-management education programs (i.e., action plans, exercise programs) should also be evaluated.

From this meta-analysis, we have shown that self-management education is associated with a reduction in hospital admissions, with no indication for detrimental effects in other outcome parameters. This would seem sufficient to justify a recommendation of self-management education in COPD. However, due to diversity in interventions, study populations, follow-up time, and outcome measures, data are still insufficient to formulate clear recommendations regarding the form and content of self-management education programs in COPD.


We are grateful to Kathryn Rice for her assistance in obtaining additional data from her study (9).


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Reference as: Hurley J, Gerkin RD, Fahy B, Robbins RA. Meta-analysis of self-management education for patients with chronic obstructive pulmonary disease. Southwest J Pulm Crit Care 2012;4:194-202. (Click here for a PDF version of the manuscript)

For the accompanying editorial "A Little Knowledge is a Dangerous Thing" click here.


June 2012 Pulmonary Case of the Month: What’s a Millet Seed Look Like?

Alexis Christie, MD

Robert Viggiano, MD

Lewis J. Wesselius, MD


Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ


History of Present Illness

A 32 year old woman presents with a week long history of dyspnea, cough, fatigue, tiredness and pruritis. She has a past medical history (PMH) of Stage IIB, nodular sclerosing Hodgkin’s disease diagnosed in January, 2011. She underwent several cycles of chemotherapy and eventually an autologous stem cell transplant in January, 2012. Her current medications include:

  • Acyclovir 800mg bid
  • Ativan 0.5mg q4h/ prn
  • Hydromorphone 8mg q4h/ prn
  • Atarax 100mg q6h/ prn
  • Compazine 10mg q6h/ prn

She had just finished a course of levofloxacin.

PMH, SH and FH

As above. She is a life-long nonsmoker and has no history of lung disease.

Physical Examination

Her physical examination was normal.

Chest X-ray

Her chest x-ray was interpreted as unchanged from previous examinations. 

Which of the following are indicated?

  1. Thoracic CT scanning
  2. PET scanning
  3. Empiric treatment with broad spectrum antibiotics
  4. All of the above

Reference as: Christie A, Viggiano R, Wesselius LJ. June 2012 pulmonary case of the month: what's a millet seed look like? Southwest J Pulm Crit Care 2012;4:182-8. (Click here for a PDF version of the case)